It is considered that pain is developed by direct stimuli from damage and invasion of tissue based on various exogenous factors, amplified by various endogenous algetic substances produced by tissue damage and results in inflammatory conditions (Tanaka et al. ed.: NEW Yakurigaku, Nankodo Co., Ltd., Apr. 15, 2002, p354-355). In addition, there is a pain caused by functional abnormality of peripheral nervous system or central nervous system, rather than tissue damage, which is referred to as a neuropathic pain.
As therapeutic drugs for these pains, a wide variety of drugs have already been known, which are largely divided from the aspects of action mechanism into opioid analgesics containing narcotic analgesics such as morphine, codeine, opium alkaloids, buprenorphine, pentazocine and the like, and antipyretic analgesics (nonnarcotic analgesics) such as aspirin, indomethacin, acetaminophen and the like. While the former provides a strong analgesic effect by acting on the opioid receptor in the central nervous system, its use is limited because it causes severe side effects and dependency. While the latter acts on peripheral tissues to bring about an anti-inflammatory and analgesic effect, the level of the action is low and various side effects may express. Furthermore, a therapeutic drug effective for a neuropathic pain associated with diabetic neuropathy, trigeminal neuropathy, herpes zoster and the like has not been found yet, and the development of a pharmaceutical agent effective for a broad range of pains, including these pains, has been desired.
In recent years, during the course of studies relating to the algetic mechanism, a receptor of capsaicin (pungent component of red pepper), known to be an algetic substance, was cloned and named as a vanilloid receptor (hereinafter to be referred to as “VR1”) (Nature, 389, p816 (1997)).
Since VR1 present in the capsaicin-sensitive sensory nerve is activated not only by a capsaicin-like substance but also by heat, acid (H+) and the like, VR1 is considered to be involved in pains and inflammations associated with various pathologies.
To be specific, when VR1 is activated by stimuli of capsaicin and the like, the cation channel opens, the membrane is depolarized and neuropeptide is released, which in turn evokes pain and inflammation. Therefore, a substance that antagonizes activation of VR1 is potentially a superior therapeutic drug for pain and inflammation. In fact, capsazepine, known to be a VR1 receptor antagonist, has been reported to show a remarkable analgesic effect in animal models (Life Science, 69, p2911 (2001)).
On the other hand, VR1 agonist capsaicin is also considered to develop intense stimuli (pain) and then induce an analgesic effect or anti-inflammatory effect. It is postulated that capsaicin binds to a receptor to continuously open the VR1 cation channel, which in turn makes the sensory nerve unresponsive to stimuli (Pharmacol. Rev. 51, p159 (1999)). Since capsaicin has been, in fact, effectively used as an analgesic for pain in diseases such as diabetic neuropathy, rheumatoid arthritis and the like, a compound (VR1 agonist) having a capsaicin-like action mechanism is also expected to be a therapeutic drug for pain and inflammation.
In addition, a report has been documented that patients with not only pain but also inflammatory bowel diseases (Crohn's disease, ulcerative colitis etc.) show high expression of VR1, and therefore, a compound having a capsaicin-like action mechanism or an action mechanism that antagonizes responses of capsaicin is expected to be a good therapeutic drug for inflammatory bowel diseases.
As diseases involving the capsaicin-sensitive sensory nerve, pruritus, allergic and nonallergic rhinitis, (e.g., hyperactive bladder) pollakiuria and incontinentia, apoplexy, irritable bowel syndrome, respiratory diseases (asthma, chronic obstructive pulmonary disease etc.), dermatitis, gastric ulcer, duodenal ulcer, functional gastrointestinal diseases such as functional dyspepsia, gastroesophageal reflux disease and the like, and the like are known, and an antiobesity action on capsaicin has been reported. Therefore, a compound having a capsaicin-like action mechanism or an action mechanism that antagonizes responses of capsaicin is also useful as a therapeutic drug for these diseases and conditions.
As mentioned above, a compound having a capsaicin-like action mechanism or an action mechanism that antagonizes, responses of capsaicin is highly expected to be a therapeutic drug for neuropathic pain, for which existing analgesics are ineffective, such as diabetic neuropathy and the like, as well as pains caused by various diseases such as rheumatoid arthritis and the like, and further, being apart from pain, a therapeutic drug for various diseases in which VR1 is involved, such as ulcerative colitis and the like.
As the vanilloid receptor antagonist, the compounds of the following formulas (a), (b), (c) and (d) are described in US 2003/0158198 A, WO 02/16317, WO 02/072536 and WO 02/08221, respectively. In addition, the compounds of the following formulas (e) and (f) are described in WO 03/014064 and WO 03/080578, respectively.
wherein X1 is N or CR1, X2 is N or CR2, X3 is N, NR3, or CR3, X4 is N or CR4, X5 is N and the like, Z1 is O and the like, Z2 is NH and the like, L is —(CH2)mO(CH2)n— and the like, m=0 and the like, n=2 and the like, and R9′ is aryl, heterocycle and the like, provided that at least one of X1, X2, X3 and X4 is N.
wherein R1 is Ar′—(CH2)m— and the like, m is 1-4, Y is O and the like, Z is NR3 and the like, R2 is hydrogen, C1-6 lower alkyl group or Ar″—(CH2)n— and the like, p is 0-4 and the like, and A is O and the like.
wherein P is phenyl or naphthyl, and n is 2 and the like.
wherein A is NRA and the like, Z is O or S, R1 and R2 are H or alkyl, and R3 and R4 are H, halogen and the like.
wherein Q is CH or N, R6 and R7 are H or methyl, X is phenylalkyl group and the like, Y is 7-hydroxy-1-naphthyl group and the like.
wherein X is O and the like, A, B, D and E are C or N, R3 and R4 are H and the like, R5 and R6 are H or alkyl and the like, n is 0-3, Y is aryl and the like.
Besides the above-mentioned, vanilloid receptor antagonists and capsaicin-like agonistic substances are known (US 2003/0158188 A, WO 03/070247, WO 02/072536, WO 02/16318, WO 02/16319, WO 00/50387, WO 03/053945, WO 03/027064). However, all of these compounds are structurally different from the compound of the formula (I) to be mentioned below.
In addition, the following compound (X-1) is a known compound (GB 2065121) and known as a thromboxane A2 synthesis enzyme inhibitor. However, it does not contain any description relating to the action mechanism described in the present invention, and while the following compounds (X-2) and (X-3) are known compounds (U.S. Pat. No. 3,535,328), it does not contain any description relating to the pharmacological effect and action mechanism described in the present invention.
Furthermore, the following compound (X-4)(described in Journal of Pharmacy and Pharmacology. 16, (8), p538-48 (1964)), the following compound (X-5) (described in Kogyo Kagaku Zasshi 68 (12), p2370-2373 (1965) and the following compounds (X-6) and (X-7) (described in Journal of Chromatography, 645(2), p233-239 (1993)) are known compounds but none of these documents contain a description relating to the pharmacological effect and action mechanism described in the present invention.
